Treatment for Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease

Abstract

A library of heterocyclic compounds has been screened to identify particular compounds that have high inhibitory capacity for the Bcl family of regulatory proteins. Compounds identified as Bcl antagonists have been further screened to select pharmaceutical agents with both high potency and high specificity for eliminating senescent cells in comparison with replicative or quiescent cells of the same tissue type. Particular structures are identified in this disclosure that eliminate senescent cells with an EC 50 in the nanomole range and a specificity around or above 100-fold. In accordance with this invention, heterocyclic compounds provided in this disclosure can be formulated for the treatment of a range of age-related conditions caused or mediated by senescent cells. Such conditions are exemplified by ophthalmic conditions, pulmonary conditions, and osteoarthritis.

1 . A method of treating a pulmonary condition mediated by senescent cells,
 the method comprising administering in or around lung tissue of the subject a pharmaceutical composition that includes a compound having a chemical structure that comprises Formula (VII) as shown below, or a phosphorylated form thereof:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently C 1  to C 4  alkyl 
         R 3 , R 4  and R 5  are independently —H or —CH 3 ; 
         R 6  and R 7  are independently alkyl or heteroalkyl, and are optionally cyclized; 
         X 1  is —F, —Br, or —OCH 3 ; 
         X 2  is —SO 2 R′ OR —CO 2 R′, where R′ is —H, —CH 3 , or —CH 2 CH 3 ; 
         X 3  is —SO 2 CF 3  or —NO 2 ; and 
         X 5  is —F, —Br, —Cl, —H, or —OCH 3 . 
       
     
     
         2 . The method of  claim 1 , wherein the compound has a chemical structure that comprises Formula (VI) as shown below, or a phosphorylated form thereof. 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently C 1  to C 4  alkyl; 
         R 3  and R 4  are independently —H or —CH 3 ; 
         R 6  and R 7  are independently alkyl or heteroalkyl, and are optionally cyclized; 
         X 1  is —F, —Br, or —OCH 3 ; 
         X 2  is —SO 2 R′ OR —CO 2 R′, where R′ is —H, —CH 3 , or —CH 2 CH 3 ; 
         X 3  is —SO 2 CF 3  or —NO 2 ; 
         X 4  is —OH or —COOH; and 
         n 1  and n 2  are independently 1, 2, or 3. 
       
     
     
         3 . The method of  claim 2 , wherein the compound has one or more of the following features in any combination:
 R 1  is isopropyl;   R 2  is methyl;   R 3  is —H;   R 4  is —H;   X 1  is —Cl;   X 2  is —SO 2 CH 3 ;   X 3  is —SO 2 CF 3 ;   X 4  is —OH;   n 1  is 2; and   n 2  is 2.   
     
     
         4 . The method of  claim 1 , wherein the compound is a phosphorylated form of Formula (VI). 
     
     
         5 . The method of  claim 1 , wherein the compound is a non-phosphorylated form of Formula (VI). 
     
     
         6 . The method of  claim 2 , wherein the compound is a phosphorylated form of Formula (VII). 
     
     
         7 . The method of  claim 2 , wherein the compound is a non-phosphorylated form of Formula (VII). 
     
     
         8 . The method of  claim 3 , wherein the compound has all of said features. 
     
     
         9 . The method of  claim 1 , wherein the pulmonary condition is idiopathic pulmonary fibrosis (IPF). 
     
     
         10 . The method of  claim 1 , wherein the pulmonary condition is chronic obstructive pulmonary disease (COPD). 
     
     
         11 . The method of  claim 2 , wherein the pulmonary condition is idiopathic pulmonary fibrosis (IPF). 
     
     
         12 . The method of  claim 2 , wherein the pulmonary condition is chronic obstructive pulmonary disease (COPD). 
     
     
         13 . The method of  claim 1 , wherein the compound is administered by inhalation as an aerosol. 
     
     
         14 . The method of  claim 2 , wherein the compound is administered by inhalation as an aerosol. 
     
     
         15 . The method of  claim 1 , wherein the compound is administered in a plurality of treatment cycles, wherein each treatment cycle independently comprises a treatment course followed by a non-treatment interval of at least 2 weeks 
     
     
         16 . The method of  claim 1 , wherein the compound is administered as a single dose followed by a non-treatment interval of at least 2 months. 
     
     
         17 . A pharmaceutical composition for treatment of a pulmonary condition,
 wherein the composition is a pharmaceutical formulation that contains a concentration of the compound shown in Formula (VI) or Formula (VII),   wherein the formulation is configured for aerosol administration of the composition into a lung of a subject in need thereof, and   wherein the formulation of the composition and the concentration of the compound in the composition configure the composition to be effective in treating the pulmonary condition by decreasing the severity of one or more signs or symptoms of the condition when administered by aerosol into the lung of the subject.   
     
     
         18 . The composition of  claim 17 , wherein the pulmonary condition is idiopathic pulmonary fibrosis (IPF). 
     
     
         19 . The composition of  claim 17 , wherein the pulmonary condition is chronic obstructive pulmonary disease (COPD). 
     
     
         20 . The composition of  claim 18 , packaged with information for administration for use of the composition for treatment of the pulmonary condition.